Sutent Dosage and Administration

Administration

Oral Administration

Dosage

Available as sunitinib malate; dosage expressed in terms of sunitinib.12

Adults

GIST

Oral

50 mg once daily for 4 consecutive weeks followed by a 2-week period without the drug.1 May continue therapy (i.e., 6-week cycles) for as long as the patient derives clinical benefit or until unacceptable toxicity occurs; in principal efficacy study, therapy was continued for a median of 5–6 cycles.2

Renal Cell Carcinoma

Oral

50 mg once daily for 4 consecutive weeks followed by a 2-week period without the drug.16 May continue therapy (i.e., 6-week cycles) for as long as the patient derives clinical benefit or until unacceptable toxicity occurs;2 in principal efficacy study, therapy was continued for a median of 11.1 months.1

PNET

Oral

37.5 mg once daily continuously (i.e., without an off-treatment period).1 May continue therapy for as long as the patient derives clinical benefit or until unacceptable toxicity occurs; in principal efficacy study, therapy was continued for a median of 4.6 months.1

In clinical studies, dosages reduced following drug-related adverse effects generally were not re-escalated, even in absence of toxicity; however, re-escalation back to previous dosage was permitted based on clinical judgment.2 Initiation of next treatment cycle could be delayed if additional time (i.e., >2 weeks) was required to recover from toxicities that developed during previous treatment cycle.2

Cardiovascular Toxicities

If manifestations of CHF develop, discontinue sunitinib.1 In patients without clinical evidence of CHF but in whom left ventricular ejection fraction (LVEF) is <50% and is reduced from baseline by >20%, interrupt therapy and/or reduce sunitinib dosage.1

In clinical studies, sunitinib was temporarily withheld following development of certain grade 2 (i.e., asymptomatic decrease in LVEF from baseline by 20% and to a level below the lower limit of normal [LVEF <50%], nonurgent ventricular paroxysmal dysrhythmia requiring intervention) or grade 3 cardiac toxicities.2 When manifestations resolved or decreased in intensity to ≤grade 1, patients who originally experienced grade 2 cardiac toxicity could resume sunitinib therapy at same dosage (if toxicity resolved within 1 week) or at 1 dose level lower than previous dosage; patients who originally experienced grade 3 cardiac toxicity could resume therapy at 1 dose level lower than previous dosage.2 Patients who developed grade 4 cardiac toxicity were required to permanently discontinue therapy.2

Hematologic Toxicity

In clinical studies, sunitinib was temporarily withheld following development of grade 3 or 4 hematologic toxicity (excluding lymphopenia).2 When manifestations resolved or decreased in intensity to ≤grade 2, patients who originally experienced grade 3 hematologic toxicity could resume sunitinib therapy at same dosage; patients who originally experienced grade 4 hematologic toxicity could resume therapy at 1 dose level lower than previous dosage.2 Patients who experienced grade 3 or 4 lymphopenia could continue therapy without interruption.2

Other Nonhematologic Toxicities

In clinical studies, sunitinib was temporarily withheld following development of grade 3 or 4 nonhematologic toxicity.2 When manifestations resolved or decreased in intensity to ≤grade 1, patients with GIST who originally experienced grade 3 nonhematologic toxicity could resume sunitinib therapy at same dosage, while those with advanced renal cell carcinoma could resume therapy at same dosage or at 1 dose level lower than previous dosage; patients who originally experienced grade 4 nonhematologic toxicity could resume therapy at 1 dose level lower than previous dosage or discontinue therapy based on clinical judgment.2

Concomitant Use with Drugs and Foods Affecting Hepatic Microsomal Enzymes

Concomitant use with potent inhibitors or inducers of CYP3A4 may alter the combined plasma concentrations of sunitinib and its primary active metabolite.1 (See Drugs and Foods Affecting Hepatic Microsomal Enzymes under Interactions.)

If concomitant use with a potent CYP3A4 inhibitor cannot be avoided, consider reducing sunitinib dosage to no less than 37.5 mg daily (in patients receiving sunitinib for GIST or advanced renal cell carcinoma) or no less than 25 mg daily (in patients receiving sunitinib for progressive, well-differentiated PNET).1

Monitor liver function tests (ALT, AST, and bilirubin concentrations) prior to initiation of sunitinib, during therapy, and as clinically indicated.1 If grade 3 or 4 hepatotoxicity occurs, temporarily interrupt therapy; if hepatotoxicity does not resolve, discontinue sunitinib.1 Do not restart sunitinib therapy in patients who subsequently experience severe changes in liver function tests or exhibit other manifestations of hepatic failure.1

Safety not established in patients with AST and/or ALT concentrations >2.5 times the ULN or, if caused by liver metastases, >5 times the ULN.1

Other Warnings and Precautions

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm;1 teratogenicity, embryotoxicity, and fetotoxicity demonstrated in animals.1 Avoid pregnancy during therapy.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Unknown whether patients with recent (i.e., within 12 months) history of cardiovascular disease (e.g., MI, severe or unstable angina, coronary or peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or TIA, pulmonary embolism) may be at a higher risk of developing drug-related left ventricular dysfunction since such patients were excluded from clinical studies.1 Weigh this risk against potential benefits of the drug.1 Carefully monitor such patients for clinical signs and symptoms of congestive heart failure during sunitinib therapy and consider baseline and periodic evaluations of LVEF.1 Also consider baseline evaluation of ejection fraction in patients without cardiac risk factors.1 (See Cardiovascular Toxicities under Dosage and Administration.)

Osteonecrosis of the Jaw (ONJ)

ONJ reported; may manifest as jaw pain, numbness or feeling of heaviness in the jaw, loosening of a tooth, toothache, or swelling or sores inside the mouth.1 Increased risk in patients with dental disease or when used concomitantly with bisphosphonate therapy.1

Perform an oral examination and appropriate preventive dentistry prior to initiation of therapy.1 If possible, avoid invasive dental procedures during therapy, particularly in patients who previously received or currently are receiving bisphosphonate therapy.1 (See Advice to Patients.)

Cases of necrotizing fasciitis, including fatalities, also reported.1 Necrotizing fasciitis occurred secondary to fistula formation and included sites such as the perineum.1 Discontinue therapy if necrotizing fasciitis occurs.1

Endocrine Effects

Adrenal toxicity (characterized histologically by hemorrhage, necrosis, congestion, hypertrophy, and inflammation) reported in animals; however, no evidence of adrenal hemorrhage or necrosis in humans.1

Pancreatitis

Microangiopathic Hemolytic Anemia

Microangiopathic hemolytic anemia reported in patients with solid tumors receiving bevacizumab and sunitinib†; cases were reversible within 3 weeks following discontinuance of both drugs without other interventions.1617 Use of bevacizumab in combination with sunitinib is notrecommended.1617

Specific Populations

Pregnancy

Lactation

Distributed into milk in rats; drug concentration up to 12-fold higher in milk than in plasma.1 Not known whether sunitinib or its primary active metabolite is distributed into human milk.1 Discontinue nursing or the drug because of potential risk in nursing infants.1

Pediatric Use

Geriatric Use

No substantial differences in safety and efficacy in patients ≥65 years of age relative to younger adults.1

Hepatic Impairment

Systemic exposure not affected by mild or moderate (Child-Pugh class A or B) hepatic impairment.1 (See Absorption: Special Populations, under Pharmacokinetics and also see Hepatic Impairment under Dosage and Administration.) Safety and efficacy not established in patients with severe (Child-Pugh class C) hepatic impairment.1

Clinical studies excluded patients with AST or ALT concentrations >2.5 times the ULN or, if due to liver metastases, >5 times the ULN.1

Renal Impairment

Systemic exposure was decreased in patients with end-stage renal disease undergoing hemodialysis.1 (See Absorption: Special Populations, under Pharmacokinetics and also see Renal Impairment under Dosage and Administration.)

Interactions for Sutent

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased combined plasma concentrations of sunitinib and its primary active metabolite).1 (See Specific Drugs and Foods under Interactions and also see Prolongation of QT Interval and Torsades de Pointes under Cautions.)

Sutent Pharmacokinetics

Absorption

Bioavailability

Food

Special Populations

In individuals with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, systemic exposure after a single dose was similar to that observed in individuals with normal hepatic function.1

In individuals with severe renal impairment (ClCr <30 mL/minute), systemic exposure after a single dose was similar to that observed in individuals with normal renal function.1

In individuals with end-stage renal disease undergoing hemodialysis, systemic exposure was decreased by 47% compared to those with normal renal function.1

Pharmacokinetics of sunitinib and its primary active metabolite are not substantially affected by age, body weight, Clcr, race, gender, or ECOG performance status.1

Distribution

Extent

Sunitinib and metabolites are distributed into milk in animals; not known whether the drug or its primary active metabolite is distributed into human milk.1

Half-life

Special Populations

Results of one pharmacokinetic study indicated a slightly longer sunitinib half-life in individuals with mild (Child-Pugh score of 5–6) or moderate (Child-Pugh score of 7–9) hepatic impairment; however, clearance of sunitinib not significantly different from that in individuals with normal hepatic function.12

Stability

Storage

Oral

Capsules

Actions

Inhibits multiple receptor tyrosine kinases (RTKs), 1245679101112 which are involved in the initiation of various cascades of intracellular signaling events that lead to cell proliferation and/or influence processes critical to cell survival and tumor progression (e.g., angiogenesis, metastasis, inhibition of apoptosis), based on the respective kinase.1246711

Risk of osteonecrosis of the jaw.1 Importance of advising patient that their clinician should examine their mouth before sunitinib therapy.1 Importance of informing dentist about sunitinib treatment prior to dental procedures.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Necessity of advising women to avoid pregnancy while receiving therapy.1 Advise pregnant women of risk to the fetus and/or of potential risk for loss of pregnancy.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.